Kaposi's sarcoma (KS) associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8) likely plays a central role in KS pathogenesis because KSHV seropositivity precedes KS and KSHV DNA is found in almost all KS lesions, whether or not there is coexisting human immunodeficiency virus (HIV) infection (Y. Chang, et al., Science, 266, 1865 (1994); P. S. Moore, et al., J. Virol., 70, 549 (1996); S.-J. Gao, et al., N. Engl. J. Med., 335, 233 (1996); P. S. Moore, Y. Chang, N. Engl. J. Med., 332, 1181 (1995)). KSHV is also associated with lymphoproliferative disorders including primary effusion lymphomas (PELs) and multicentric Castleman's disease (E. Cesarman, et al., Blood, 86, 2708 (1995); M. B. Rettig, et al., Science, 276, 1851 (1997); J. Soulier, et al., Blood, 86, 1276 (1995); E. Cesarman, et al., N. Engl. J. Med., 332, 1186 (1995)).
Similar to the gamma-1 herpesvirus Epstein-Barr virus (EBV), KSHV infection in tumor tissue or lymphoma derived cell lines is predominantly latent. Latently infected cells have multiple copies of circularized KSHV DNA maintained as episomes (E. Cesarman, et al., Blood, 86, 2708 (1995); M. B. Rettig, et al., Science, 276, 1851 (1997); J. Soulier, et al., Blood, 86, 1276 (1995); E. Cesarman, Y. Chang, P. S. Moore, J. W. Said, D. M. Knowles, N. Engl. J. Med., 332, 1186 (1995); L. L. Decker, et al., J. Exp. Med., 184, 283 (1996). The EBV EBNA1 protein mediates efficient episome persistence through a cis-acting 1.8 kb EBV DNA sequence termed origin of plasmid replication (oriP) (J. Yates, N. Warren, D. Reisman, B. Sugden, Proc. Natl. Acad. Sci. USA, 81, 3806 (1984); J. L. Yates, N. Warren, B. Sugden, Nature, 313, 812 (1985); D. R. Rawlins, G. Milman, S. D. Hayward, G. S. Hayward, Cell, 42, 859 (1985)). The primate transforming herpes virus saimiri (HVS), which is a rhadino virus, also has a cis-acting sequence that enables efficient persistence of episomes in HVS infected cells (S.-H. Kung, P. G. Medveczky, J. Virol., 70, 1738 (1996)). However, KSHV has no obvious homology to the HVS cis-acting DNA and a trans-acting EBNA1 homolog or analog has not been identified in HVS or other gamma-2 herpesviruses.
KSHV open reading frame (ORF) 73 encodes the latency-associated nuclear antigen (LANA, LNA, or LNA1) which is predicted to be 1162 amino acids and lacks a known function (Y. Chang, et al., Science, 266, 1865 (1994); P. S. Moore, et al., J. Virol., 70, 549 (1996); S.-J. Gao, et al., N. Engl. J. Med., 335, 233 (1996); P. S. Moore, Y. Chang, N. Engl. J. Med., 332, 1181 (1995); J. J. Russo, et al., Proc. Natl. Acad. Sci. USA, 93, 14862 (1996); P. Kellam, et al., J. of Human Virol., 1, 19 (1997); L. Rainbow, et al., J. Virol., 71, 5915 (1997); D. H. Kedes, M. Lagunoff, R. Renne, D. Ganem, J. Clin. Invest., 100, 2606 (1997); F. Neipel, J. C. Albrecht, B. Fleckenstein, J. Virol., 71, 4187 (1997)). A homologous open reading frame exists in other gamma-2 herpesviruses such as, but not limited to, HV saimiri and MHV68. (J. C. Albrecht, et al., J. Virol., 66, 5047 (1992); H. W. Virgin IV, et al., J. Virol., 71, 5894 (1997)). LANA is reactive with most KSHV-immune sera which detect LANA in KSHV infected PEL cells and KS spindle cells (P. Kellam, et al., J. of Human Virol., 1, 19 (1997); L. Rainbow, et al., J. Virol., 71, 5915 (1997); D. H. Kedes, M. Lagunoff, R. Renne, D. Ganem, J. Clin. Invest., 100, 2606 (1997); F. Neipel, J. C. Albrecht, B. Fleckenstein, J. Virol., 71, 4187 (1997); S. J. Gao, et al., Nature Medicine, 2, 925 (1996); D. H. Kedes, et al., Nature Medicine, 2, 918 (1996); D. Jones, et al., N. Engl. J. of Med., 339, 444 (1998); R. Renne, et al., Nature Medicine, 2, 342 (1996); L. Szekely, et al., J. of General Virology, 79, 1445 (1998)).